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Molecular and Cellular Biology, May 2006, p. 3966-3975, Vol. 26, No. 10
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.10.3966-3975.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Ral Is both Necessary and Sufficient for the Inhibition of Myeloid Differentiation Mediated by Ras

Nader Omidvar,* Lorna Pearn, Alan K. Burnett, and Richard L. Darley

Department of Haematology, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, United Kingdom

Received 27 July 2005/ Returned for modification 6 September 2005/ Accepted 20 February 2006

Hyperactivation of Ras is one of the most common abnormalities in acute myeloid leukemia. In experimental models, Ras inhibits myeloid differentiation, which is characteristic of leukemia; however, the mechanism through which it disrupts hematopoiesis is poorly understood. In multipotent FDCP-mix cells, Ras inhibits terminal neutrophil differentiation, thereby indefinitely extending their proliferative potential. Ras also strongly promotes the sensitivity of these cells to granulocyte-macrophage colony-stimulating factor (GM-CSF). Using this model, we have dissected the signaling elements downstream of Ras to determine their relative contribution to the dysregulation of hematopoiesis. Cells expressing Ras mutants selectively activating Raf (Ras*T35S) or phosphatidylinositol 3-kinase (Ras*Y40C) did not significantly affect differentiation or proliferative capacity, whereas Ras*E37G (which selectively activates RalGEFs) perpetuated proliferation and blocked neutrophil development in a manner similar to that of Ras. Correspondingly, expression of constitutively active versions of these effectors confirmed the overriding importance of Ral guanine nucleotide exchange factors. Cells expressing Ras demonstrated hyperactivation of Ral, which itself was able to exactly mimic the phenotype of Ras, including hypersensitivity to GM-CSF. Conversely, dominant negative Ral promoted spontaneous neutrophil development. Ral, in turn, appears to influence differentiation through multiple effectors. These data show, for the first time, the importance of Ral in regulating differentiation and self-renewal in hematopoietic cells.

* Corresponding author. Present address: Cardiff School of Biosciences, Cardiff University, Museum Avenue, Cardiff, United Kingdom. Phone: (44) 2920 879115. Fax: (44) 2920 876328. E-mail: OmidvarN{at}cf.ac.uk.

Molecular and Cellular Biology, May 2006, p. 3966-3975, Vol. 26, No. 10
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.10.3966-3975.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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